Narcolepsy is a debilitating neurological sleep disorder in which the primary symptoms are excessive daytime sleepiness, sleep attacks, frequent and sudden attacks of cataplexy, and hypnagogic hallucinations. The disease appears to be a disorder of REM sleep because some narcoleptic symptoms are components of REM sleep which are somehow encroaching into the waking state. Currently, it is hypothesized that the inappropriate intrusions of REM components are due to hyperactive central cholinergic mechanisms influencing excitability of pontine neuronal mechanisms controlling the various components of REM sleep. We are proposing a combination of neuroanatomical, neurophysiological and receptor binding studies to examine more closely the mechanisms by which the brainstem cholinergic system influences REM sleep. In the first experiment we will use a combination of retrograde (WGA-HRP and Fluorogold, a fluorescent retrograde marker), anterograde (triated amino acid transport) and choline acetyltransferase immunolabelling techniques to determine the source of the cholinergic input to the medial pontine reticular formation, an area which has traditionally been implicated in REM sleep generation. In the second experiment we will monitor the sleep-related discharge of the brainstem cholinergic neurons located in the pedunculopontine and lateral dorsal tegmental nuclei. Immunohistochemical ChAT labelling and antidromic studies will serve to strengthen the possibility that cholinergic neurons were recorder. Thirdly, we will conduct a series of experiments to determine whether a genetic strain of rats with cholinergic hyperactivity demonstrate increased REM sleep. In these studies we will correlate REM sleep levels with muscarinic receptor binding in several brain regions including the brainstem. These studies will enable us to examine the receptor mechanisms involved in REM sleep generation.
Showing the most recent 10 out of 14 publications
